Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis

Jaeken, Jaak; Wadman, S. K.; Durán, Marinus; Vansprang, Fj.; Beemer, F. A.; Holl, Ra.; Theunissen, Pm.; Cock, Peter de; Vandenbergh, F.; Vincent, Marie‐Françoise; Berghe, Georges

doi:10.1007/bf00445919

Cited by 129 publications

(90 citation statements)

References 15 publications

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“…Of these, the most important factors could be the neurotoxic effects of accumulated succinylpurines. 3 In both reported patients, a low S-Ado/SAICAr ratio of 1.6 was found, in agreement with the prediction of a severe phenotype. Other biochemical factors are the deficient synthesis of purine nucleotides and the impairment of the purine nucleotide cycle that contribute to the neurobehavioral profile in ADSL deficiency.…”

Section: Figuresupporting

confidence: 81%

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Misleading behavioural phenotype with adenylosuccinate lyase deficiency

et al. 2008

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Adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features and are usually discovered during screens for unexplained encephalopathy using the Bratton -Marshall assay that reveals the excretion of the succinylaminoimidazolecarboxamide riboside (SAICAr). Here, we report on two sisters aged 11 and 12 years presented with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combined excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that gave a behavioural profile mimicking Angelman syndrome. Both patients had an increased succinyladenosine/SAICAr ratio of 1.6, and exhibited a novel homozygous missense mutation (c.674T4C; p.Met225Thr) in the exon 6 of the ADSL gene. We suggest that these clinical features might be a new presentation of adenylosuccinate lyase deficiency. On the basis of this observation, although adenylosuccinate lyase deficiency is a rare disorder, this diagnosis should be considered in patients with mental retardation and a behavioural profile suggestive of Angelman syndrome.

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Section: Figuresupporting

confidence: 81%

“…This suggests that SAICAr is the offending compound, and that S-Ado could counteract its toxic effects. 3 However, these results show a high level of variability and cannot always be exactly correlated with the clinical features.…”

Section: Introductionmentioning

confidence: 91%

Misleading behavioural phenotype with adenylosuccinate lyase deficiency

et al. 2008

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“…Importantly, partial loss-of-function mutations on the human gene encoding the enzyme ADSL cause ADSL deficiency, a rare Mendelian disease with mental retardation and seizures as typical symptoms (Georges and Van den Berghe 1984;Jaeken et al 1988; Van den Berghe et al 1997). To date, there is no treatment with proven clinical efficacy for this disease despite a variety of therapeutic attempts (Jaeken et al 1988;Salerno et al 1998Salerno et al , 2002Ciardo et al 2001;Jurecka et al 2008). For such essential gene-related loss-of- ES indicates essential gene and RP indicates rescuing partner.…”

Section: Loss-of-function Therapy For the Loss-of-function Adsl Diseasementioning

confidence: 99%

“…Of particular interest was the gene encoding adenylosuccinate lyase, an enzyme in the purine de novo synthesis pathway. Partial loss-of-function mutations on this gene in humans cause adenylosuccinate lyase deficiency (ADSL; OMIM 103050), a rare Mendelian disorder with mental retardation and seizures as typical symptoms (Georges and Van den Berghe 1984;Jaeken et al 1988;Van den Berghe et al 1997). Accordingly, we suggested a loss-of-function therapeutic strategy to suppress the phenotypes of ADSL deficiency, and a proof-of-principle test of the strategy in the nematode C. elegans showed promising results.…”

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confidence: 99%

The nonessentiality of essential genes in yeast provides therapeutic insights into a human disease

et al. 2016

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Essential genes refer to those whose null mutation leads to lethality or sterility. Theoretical reasoning and empirical data both suggest that the fatal effect of inactivating an essential gene can be attributed to either the loss of indispensable core cellular function (Type I), or the gain of fatal side effects after losing dispensable periphery function (Type II). In principle, inactivation of Type I essential genes can be rescued only by re-gain of the core functions, whereas inactivation of Type II essential genes could be rescued by a further loss of function of another gene to eliminate the otherwise fatal side effects. Because such loss-of-function rescuing mutations may occur spontaneously, Type II essential genes may become nonessential in a few individuals of a large population. Motivated by this reasoning, we here carried out a systematic screening for Type II essentiality in the yeast Saccharomyces cerevisiae. Large-scale whole-genome sequencing of essentiality-reversing mutants reveals 14 cases whereby the inactivation of an essential gene is rescued by loss-of-function mutations on another gene. In particular, the essential gene encoding the enzyme adenylosuccinate lyase (ADSL) is shown to be Type II, suggesting a loss-of-function therapeutic strategy for the human disorder ADSL deficiency. A proof-of-principle test of this strategy in the nematode Caenorhabditis elegans shows promising results.

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“…Since their original description, patients B and C have developed a progressively more pronounced muscular atrophy and growth failure, which became apparent from the age of about 2 yr. Moreover, seizures have appeared between 4 and 5 yr of age (4). X-ray CT-scan of the brain revealed hypoplasia of the cerebellar vermis.…”

Section: Patientsmentioning

confidence: 99%

Regional Brain Glucose Utilization in Adenylosuccinase-Deficient Patients Measured by Positron Emission Tomography

Volder¹,

Jaeken²,

Berghe³

et al. 1988

Pediatr Res

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ABSTRACT. Regional brain glucose utilization was investigated by positron emission tomography with fluorodeoxyglucose in three children with adenylosuccinase deficiency. A consistent pattern was found in the three patients, namely a marked decrease of fluorodeoxyglucose uptake in all gray structures, with the exception of the cerebellum, which was minimally affected. Anomalies predominated in the cerebral cortex, particularly in the anterior regions; they were less pronounced in thalamus and basal ganglia. Adenylosuccinase deficiency is a recently described inborn error of metabolism, the first reported enzyme deficiency involving the de novo synthesis of purine nucleotides (1). Adenylosuccinase (adenylosuccinate lyase: E.C. 4.3.2.2.) catalyses two steps in purine synthesis ( Fig. 1): the conversion of SAICAR into AICAR, and that of S-AMP into AMP. Affected patients display psychomotor retardation accompanied by autistic features. The enzyme defect is manifested by the presence in cerebrospinal fluid, plasma, and urine of two normally undetectable compounds, SAICAriboside and succinyladenosine (S-adenosine). These are the products of the dephosphorylation, by cytosolic 5'-nucleotidase (2), of the two substrates of adenylosuccinase. As in other inborn errors of metabolism affecting psychomotor Received January 18, 1988; accepted April 18, 1988 development, the relationship between the enzyme defect and the neurologic dysfunction is poorly understood.Our study was undertaken as an attempt to gain insight into the pathophysiology of the disease and to localize the regions of the brain where the enzyme defect exerts its deleterious effects. Inasmuch as glucose, with oxygen, is the main substrate of the brain at all ages, regional uptake of a glucose analog in this tissue provides an index of local neural function (3). PATIENTSThe three adenylosuccinase-deficient patients A, B and C, were described previously (1). At the time of study, they were aged 3.5, 7, and 5 yr, respectively. The cardinal symptoms were a profound psychomotor retardation (developmental age between 5 and 7 months with a slightly better gross motor performance), accompanied by autistic traits. Since their original description, patients B and C have developed a progressively more pronounced muscular atrophy and growth failure, which became apparent from the age of about 2 yr. Moreover, seizures have appeared between 4 and 5 yr of age (4). X-ray CT-scan of the brain revealed hypoplasia of the cerebellar vermis. Control studies were performed in 10 normal adult volunteers aged 20-22 yr and in three children with normal IQ and minimal neurologic symptoms (aged 5, 14, and 15 yr). Clinical diagnoses in those cases were, respectively, hysteria (retrospective diagnosis), mild behavioral anomalies of unknown origin, and well-equilibrated temporal epilepsy. The results were also compared to those obtained in a 17-yr-old girl with poorly equilibrated PKU, in whom blood phenylalanine levels had been consistently higher than 20 mg/100ml for several years and w...

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Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis

Cited by 129 publications

References 15 publications

Misleading behavioural phenotype with adenylosuccinate lyase deficiency

Misleading behavioural phenotype with adenylosuccinate lyase deficiency

The nonessentiality of essential genes in yeast provides therapeutic insights into a human disease

Regional Brain Glucose Utilization in Adenylosuccinase-Deficient Patients Measured by Positron Emission Tomography

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